Adenosine 3'5'-cyclic phosphate (cyclic AMP) mediates hormone action by activation of protein kinase. Structural analogs of cyclic AMP which retain the conformational and electronic properties of its ribofuranoside-cyclic phosphate ring system are potent activators of protein kinase. Cyclic AMP is a high energy phosphate, and this thermodynamic behavior is a consequence of the ribofuranoside-cyclic phosphate ring system. The proposed research will investigate the relationship between the structure of this ring system and its thermodynamic behavior so that the conformational and electronic requirements for activation of protein kinase by cyclic AMP can be elucidated. Structural analogs of the bicyclic ring system will be prepared so that the effects of electrostatic and dipolar interactions, trans-ring fusion, hybridization of ester oxygen atoms, and molecular conformation and rigidity can be separately examined. Professor Charles Coulter of the University of Chicago will determine the structure of pertinent analogs by x-ray crystallography so that thermodynamics of hydrolysis, biochemical activity and structure can be correlated.